Biology subjects

Dittmar, M.

Publications and source records attributed to Dittmar, M..

5 recordsLinked to original sources

bioRxiv2026

Natural sleep, but not propofol-induced anesthesia preserves spatial and procedural memory consolidation

Propofol-induced general anesthesia and natural sleep are both associated with GABA-A-ergic inhibition and slow-wave activity. Whereas sleep actively supports memory consolidation, consolidation may be disrupted during anesthesia. Here, we compared EEG and memory data from 19 participants undergoing surgery under propofol-induced anesthesia with data from 17 participants taking a nap. In both groups, participants completed a hippocampus-dependent spatial memory task (Virtual Water Maze) and a procedural memory task (Mirror Tracing) before (pre) and after (post) an interval filled with either anesthesia or sleep. Performance declined from pre to post in the propofol group for both tasks, whereas it remained stable in the sleep group. Slow oscillations (SO) occurred during both non-REM sleep and propofol-induced anesthesia. However, only during non-REM sleep did SOs show increased spindle activity during the SO upstate. Together, these findings suggest that propofol anesthesia disrupts memory consolidation, most likely because SOs under anesthesia lack the spindle coupling that mediates the hippocampal-neocortical information transfer underlying systems memory consolidation.

neuroscience↗

bioRxiv2023

Evolutionary arms race between SARS-CoV-2 and interferon signaling via dynamic interaction with autophagy.

SARS-CoV-2 emerged, and is evolving to efficiently infect humans worldwide. SARS-CoV-2 evades early innate recognition, interferon signaling activated only in bystander cells. This balance of innate activation and viral evasion has important consequences, but the pathways involved are incompletely understood. Here we find that autophagy genes regulate innate immune signaling, impacting the basal set point of interferons, and thus permissivity to infection. Mechanistically, autophagy genes negatively regulate MAVS, and this low basal level of MAVS is efficiently antagonized by SARS-CoV-2 ORF9b, blocking interferon activation in infected cells. However, upon loss of autophagy increased MAVS overcomes ORF9b-mediated antagonism suppressing infection. This has led to the evolution of SARS-CoV-2 variants to express higher levels of ORF9b, allowing SARS-CoV-2 to replicate under conditions of increased MAVS signaling. Altogether, we find a critical role of autophagy in the regulation of innate immunity and uncover an evolutionary trajectory of SARS-CoV-2 ORF9b to overcome host defenses.

microbiology↗

bioRxiv2021

Pyrimidine biosynthesis inhibitors synergize with nucleoside analogs to block SARS-CoV-2 infection

The ongoing COVID-19 pandemic has highlighted the dearth of approved drugs to treat viral infections, with only [~]90 FDA approved drugs against human viral pathogens. To identify drugs that can block SARS-CoV-2 replication, extensive drug screening to repurpose approved drugs is underway. Here, we screened [~]18,000 drugs for antiviral activity using live virus infection in human respiratory cells. Dose-response studies validate 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Amongst these drug candidates are 16 nucleoside analogs, the largest category of clinically used antivirals. This included the antiviral Remdesivir approved for use in COVID-19, and the nucleoside Molnupirivir, which is undergoing clinical trials. RNA viruses rely on a high supply of nucleoside triphosphates from the host to efficiently replicate, and we identified a panel of host nucleoside biosynthesis inhibitors as antiviral, and we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogs synergistically inhibits SARS-CoV-2 infection in vitro and in vivo suggesting a clinical path forward.

microbiology↗

bioRxiv2020

Drug repurposing screens reveal FDA approved drugs active against SARS-Cov-2

There are an urgent need for antivirals to treat the newly emerged SARS-CoV-2. To identify new candidates we screened a repurposing library of ~3,000 drugs. Screening in Vero cells found few antivirals, while screening in human Huh7.5 cells validated 23 diverse antiviral drugs. Extending our studies to lung epithelial cells, we found that there are major differences in drug sensitivity and entry pathways used by SARS-CoV-2 in these cells. Entry in lung epithelial Calu-3 cells is pH-independent and requires TMPRSS2, while entry in Vero and Huh7.5 cells requires low pH and triggering by acid-dependent endosomal proteases. Moreover, we found 9 drugs are antiviral in lung cells, 7 of which have been tested in humans, and 3 are FDA approved including Cyclosporine which we found is targeting Cyclophilin rather than Calcineurin for its antiviral activity. These antivirals reveal essential host targets and have the potential for rapid clinical implementation.

microbiology↗

bioRxiv2020

Viral-Induced Alternative Splicing of Host Genes Promotes Influenza Replication

Viral infection induces the expression of numerous host genes that impact the outcome of infection. Here we show that infection of human lung epithelial cells with Influenza A virus (IAV) also induces a broad program of alternative splicing of host genes. While these splicing-regulated genes are not enriched for canonical regulators of viral infection, we find that many of these genes do impact replication of IAV. Moreover, specific inhibition of the IAV-induced splicing in several cases also attenuates viral infection. We further show that approximately a quarter of the IAV-induced splicing events are regulated by hnRNP K, a host protein that required for efficient splicing of the IAV M transcript in nuclear speckles. Notably, we find that hnRNP K accumulates in nuclear speckles upon IAV infection, which is likely to alter the accessibility of hnRNP K for host transcripts thereby leading to a program of host splicing changes that promote IAV replication.

molecular biology↗